What happens when cardiac Na channel function is compromised? 2. Numerical studies of the vulnerable period in tissue altered by drugs

• Published in: Cardiovascular research 2003-03, Vol.57 (4), p.1062-1071
• Main Authors: STARMER, C. Frank, GRANT, A. O, COLATSKY, T. J
• Format: Article
• Language: English
• Subjects: Action Potentials - drug effects; Anti-Arrhythmia Agents - pharmacology; Antiarythmic agents; Biological and medical sciences; Cardiovascular system; Computer Simulation; Heart Conduction System - drug effects; Humans; Medical sciences; Models, Cardiovascular; Pharmacology. Drug treatments; Refractory Period, Electrophysiological; Sodium Channel Blockers - pharmacology; Sodium Channels - physiology
• ISSN: 0008-6363; 1755-3245
• DOI: 10.1016/S0008-6363(02)00727-7

The fate of an impulse arising from stimulation is determined by the ability of the wave front to recruit sufficient Na channels from adjacent cells. Previous numerical studies of mutant Na channels revealed both the velocity of a conditioning wave and the recruiting capacity of the front as determinants of the vulnerable period (VP), an interval within which excitation results in unidirectional conduction. Drugs that block excitatory Na channels in a voltage dependent manner, such as antiarrhythmics, abused substances and antidepressants, slow the restoration of Na conductance trailing an action potential and are associated with proarrhythmia and sudden cardiac death. We hypothesized that drug-induced slowing of Na conductance recovery would flatten the Na conductance restoration gradient thereby reducing the recruiting capacity of a front, extending the VP and increasing the probability of unidirectional propagation. In a cable of ventricular cells, we explored the sensitivity of the VP to voltage-dependent blockade. While varying the unbinding time constant from 100 ms to 5 s, we measured the Na conductance restoration gradient, the liminal length, the refractory period (RP) and the VP. Reducing the rate of drug unbinding flattened the restoration gradient, diminished the recruiting capacity of a premature impulse and extended the liminal length, RP and the VP. The VP was linearly dependent on the drug unbinding time constant. Rapidly unbinding drugs (time constant